tbuckley/cabot-search huggingface dataset:
Global analysis of suppressor mutations that rescue human genetic defects
Authors: Betül Ünlü, Carles Pons, Uyen Linh Ho, Amandine Batté, Patrick Aloy, Jolanda van Leeuwen
Journal: Genome Medicine (2023)

Abstract Background Genetic suppression occurs when the deleterious effects of a primary “query” mutation, such as a disease-causing mutation, are rescued by a suppressor mutation elsewhere in the genome. Methods To capture existing knowledge on suppression relationships between human genes, we examined 2,400 published papers for potential interactions identified through either genetic modification of cultured human cells or through association studies in patients. Results The resulting network encompassed 476 unique suppression interactions covering a wide spectrum of diseases and biological functions. The interactions frequently linked genes that operate in the same biological process. Suppressors were strongly enriched for genes with a role in stress response or signaling, suggesting that deleterious mutations can often be buffered by modulating signaling cascades or immune responses. Suppressor mutations tended to be deleterious when they occurred in absence of the query mutation, in apparent contrast with their protective role in the presence of the query. We formulated and quantified mechanisms of genetic suppression that could explain 71% of interactions and provided mechanistic insight into disease pathology. Finally, we used these observations to predict suppressor genes in the human genome. Conclusions The global suppression network allowed us to define principles of genetic suppression that were conserved across diseases, model systems, and species. The emerging frequency of suppression interactions among human genes and range of underlying mechanisms, together with the prevalence of suppression in model organisms, suggest that compensatory mutations may exist for most genetic diseases.
Mean global DNA methylation serves as independent prognostic marker in IDH-wildtype glioblastoma
Authors: Alicia Eckhardt, Richard Drexler, Melanie Schoof, Nina Struve, David Capper, Claudius Jelgersma, Julia Onken, Patrick N Harter, Katharina J Weber, Iris Divé, Kai Rothkamm, Konstantin Hoffer, Lukas Klumpp, Katrin Ganser, Cordula Petersen, Franz Ricklefs, Malte Kriegs, Ulrich Schüller
Journal: Neuro-Oncology (2023)

Abstract Background The IDH-wildtype glioblastoma (GBM) patients have a devastating prognosis. Here, we analyzed the potential prognostic value of global DNA methylation of the tumors. Methods DNA methylation of 492 primary samples and 31 relapsed samples, each treated with combination therapy, and of 148 primary samples treated with radiation alone were compared with patient survival. We determined the mean methylation values and estimated the immune cell infiltration from the methylation data. Moreover, the mean global DNA methylation of 23 GBM cell lines was profiled and correlated to their cellular radiosensitivity as measured by colony formation assay. Results High mean DNA methylation levels correlated with improved survival, which was independent from known risk factors (MGMT promoter methylation, age, extent of resection; P = 0.009) and methylation subgroups. Notably, this correlation was also independent of immune cell infiltration, as higher number of immune cells indeed was associated with significantly better OS but lower mean methylation. Radiosensitive GBM cell lines had a significantly higher mean methylation than resistant lines (P = 0.007), and improved OS of patients treated with radiotherapy alone was also associated with higher DNA methylation (P = 0.002). Furthermore, specimens of relapsed GBM revealed a significantly lower mean DNA methylation compared to the matching primary tumor samples (P = 0.041). Conclusions Our results indicate that mean global DNA methylation is independently associated with outcome in glioblastoma. The data also suggest that a higher DNA methylation is associated with better radiotherapy response and less aggressive phenotype, both of which presumably contribute to the observed correlation with OS.
Incidence and Predictors of Esophagogastric Varices Bleeding in Patients with Hepatocellular Carcinoma in Lenvatinib
Authors: Massimo Iavarone, Eleonora Alimenti, Toshifumi Tada, Shigeo Shimose, Goki Suda, Changhoon Yoo, Caterina Soldà, Fabio Piscaglia, Giulia Tosetti, Fabio Marra, Caterina Vivaldi, Fabio Conti, Marta Schirripa, Hideki Iwamoto, Takuya Sho, So Heun Lee, Mario Domenico Rizzato, Matteo Tonnini, Margherita Rimini, Claudia Campani, Gianluca Masi, Francesco Foschi, Mariangela Bruccoleri, Takumi Kawaguchi, Takashi Kumada, Atsushi Hiraoka, Masanori Atsukawa, Shinya Fukunishi, Toru Ishikawa, Kazuto Tajiri, Hironori Ochi, Satoshi Yasuda, Hidenori Toyoda, Takeshi Hatanaka, Satoru Kakizaki, Kazuhito Kawata, Fujimasa Tada, Hideko Ohama, Norio Itokawa, Tomomi Okubo, Taeang Arai, Michitaka Imai, Atsushi Naganuma, Andrea Casadei-Gardini, Pietro Lampertico
Journal: Liver Cancer (2023)

Lenvatinib is indicated for the forefront treatment of advanced hepatocellular carcinoma (aHCC), but its use may be limited by the risk of esophagogastric varices (EGV) bleeding. This study assessed the prevalence, predictors, and complications of EGV in aHCC patients treated with lenvatinib.
MRI Using Gadoxetic Acid in the Work-Up of Liver Nodules Not Conclusively Benign in Budd-Chiari Syndrome: A Prospective Long-Term Follow-Up
Authors: Ángeles García-Criado, Jordi Rimola, Susana Seijo, Anna Darnell, Ernest Belmonte, Víctor Sapena, Julián Moreno-Rojas, Valeria Pérez, Virginia Hernández-Gea, Carmen Ayuso, María Reig, Juan Carlos García-Pagán, Jordi Bruix
Journal: Liver Cancer (2023)

&lt;b&gt;&lt;i&gt;Introduction:&lt;/i&gt;&lt;/b&gt; The incidence of hepatocellular carcinoma (HCC) in Budd-Chiari syndrome (BCS) is unknown and there is no validated diagnostic work-up to define the liver nodules with arterial phase hyperenhancement (APHE), suggesting malignancy. This prospective study evaluates HCC incidence in a Western cohort of patients with BCS and assesses the performance of MRI with hepatobiliary contrast (HB-MRI) for nodule characterization. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; Patients with BCS followed in our hospital were prospectively evaluated by MRI with extracellular contrast (EC-MRI). Nodules with APHE categorized as non-conclusively benign by 2 radiologists were studied by HB-MRI and reviewed by 2 radiologists blinded to the EC-MRI results. A new EC-MRI 1 year later and clinical, analytical, and sonographic follow-up every 6 months for a median of 10 years was performed. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; A total of 55 non-conclusively benign nodules with APHE were detected at EC-MRI in 41 patients. While 32 of them were suggestive of HCC by EC-MRI, all the 55 nodules showed increased uptake of hepatobiliary contrast. An unequivocal central scar was seen in 12/55 nodules at HB-MRI regardless of it was not detected on the EC-MRI. None of the nodules was hypointense in the hepatobiliary phase (HBP). HCC was not detected during a median of 10 years of follow-up. &lt;b&gt;&lt;i&gt;Conclusions:&lt;/i&gt;&lt;/b&gt; Detection of nodules with APHE is frequent in patients with BCS, but HCC is rare in Western patients with BCS. While EC-MRI may detect nodules suggesting malignancy, the identification of contrast uptake in the HBP at HB-MRI may help categorize them as benign.
A nanoparticle platform for combined mucosal healing and immunomodulation in inflammatory bowel disease treatment
Authors: Valentina Marotti, Yining Xu, Cécilia Bohns Michalowski, Wunan Zhang, Inês Domingues, Hafsa Ameraoui, Tom G. Moreels, Pieter Baatsen, Matthias Van Hul, Giulio G. Muccioli, Patrice D. Cani, Mireille Alhouayek, Alessio Malfanti, Ana Beloqui
Journal: Bioactive Materials (2023)

Current treatments for inflammatory bowel disease (IBD) treatment consist of anti-inflammatory products. In this study, we sought to induce the physiological secretion of glucagon-like peptide 2, a peptide with intestinal growth-promoting activity, via nanoparticles while simultaneously providing with immunomodulation by tailoring the nanoparticle surface. To this end, we developed hybrid lipid hyaluronate-KPV conjugated nanoparticles loaded with teduglutide for combination therapy in IBD. The nanocarriers induced (or did not induce) immunosuppression depending on the presence (or absence) of a hyaluronan-KPV functionalization. This strategy holds promise as a nanoparticle platform for combined mucosal healing and immunomodulation in IBD treatment.
Video Tutorials to Empower Caregivers of Ill Children and Reduce Health Care Utilization
Authors: Liv Borch-Johnsen, Caroline Gren, Stine Lund, Fredrik Folke, Morten Schrøder, Marianne Sjølin Frederiksen, Freddy Lippert, Annette Kjær Ersbøll, Gorm Greisen, Dina Cortes
Journal: JAMA Network Open (2023)

Importance Young children often fall ill, leading to concern among their caregivers and urgent contact with health care services. Objective To assess the effectiveness and safety of video tutorials to empower caregivers in caring for acutely ill children. Design, Setting, and Participants Caregivers calling the out-of-hours Medical Helpline 1813 (MH1813), Emergency Medical Services Capital Region, Denmark, and their children aged 0.5 to 11.9 years were randomized to video tutorials (intervention) or telephone triage by a nurse or physician (control) from October 2020 to December 2021 and followed up for 72 hours blinded to the intervention. Data were analyzed from March to July 2022. Intervention The intervention group had the call disconnected before telephone triage and received video tutorials on managing common symptoms in acutely ill children and when to seek medical help. Caregivers could subsequently call MH1813 for telephone triage. Main outcomes and measures The primary outcome was caregivers’ self-efficacy, reported in an electronic survey the following day. Secondary outcomes were satisfaction, child status, assessment by a general practitioner or physician at the hospital, telephone triage, and adverse events during the 72-hour follow-up period. Results In total, 4686 caregivers and children were randomized to intervention (2307 participants) or control (2379 participants), with a median (IQR) child age of 2.3 (1.3-5.1) years and 53% male distribution in both groups (2493 participants). Significantly more caregivers in the intervention group reported high self-efficacy (80% vs 76%; crude odds ratio [OR], 1.30; 95% CI, 1.01-1.67; P = .04). The intervention group received fewer telephone triages during follow-up (887 vs 2374 in the control group). Intention-to-treat analysis showed no difference in secondary outcomes, but per-protocol subanalysis showed fewer hospital assessments when caregivers watched video tutorials (27% vs 35%; adjusted OR, 0.67; 95% CI, 0.55-0.82). Randomization to video tutorials did not increase adverse outcomes. Conclusions and relevance In this randomized clinical trial, offering caregivers video tutorials significantly and safely increased self-efficacy and reduced use of telephone triage. Children had fewer hospital assessments when caregivers watched videos. This suggests a future potential of health care information to empower caregivers and reduce health care utilization. Trial Registration ClinicalTrials.gov Identifier: NCT04301206
Hybrid mRNA Nano Vaccine Potentiates Antigenic Peptide Presentation and Dendritic Cell Maturation for Effective Cancer Vaccine Therapy and Enhances Response to Immune Checkpoint Blockade
Authors: Lu Shi, Jingxing Yang, Ying Nie, Yizhou Huang, Hongchen Gu
Journal: Advanced Healthcare Materials (2023)

Cancer vaccines combined with immune checkpoint blockades (ICB) represent great potential application, yet the insufficient tumor antigen presentation and immature dendritic cells hinder improved efficacy. Here, a hybrid nano vaccine composed by hyper branched poly(beta-amino ester), modified iron oxide nano adjuvant and messenger RNA (mRNA) encoded with model antigen ovalbumin (OVA) is presented. The nano vaccine outperforms three commercialized reagents loaded with the same mRNA, including Lipofectamine MessengerMax, jetPRIME, and in vivo-jetRNA in promoting dendritic cells' transfection, maturation, and peptide presentation. In an OVA-expressing murine model, intratumoral administration of the nano vaccine significantly induced macrophages and dendritic cells' presenting peptides and expressing co-stimulatory CD86. The nano vaccine also elicited strong antigen-specific splenocyte response and promoted CD8+ T cell infiltration. In combination with ICB, the nano vaccine aroused robust tumor suppression in murine models with large tumor burdens (initial volume >300 mm
Hybrid Epigenomes Reveal Extensive Local Genetic Changes to Chromatin Accessibility Contribute to Divergence in Embryonic Gene Expression Between Species
Authors: Hannah R Devens, Phillip L Davidson, Maria Byrne, Gregory A Wray
Journal: Molecular Biology and Evolution (2023)

Chromatin accessibility plays an important role in shaping gene expression, yet little is known about the genetic and molecular mechanisms that influence the evolution of chromatin configuration. Both local (cis) and distant (trans) genetic influences can in principle influence chromatin accessibility and are based on distinct molecular mechanisms. We, therefore, sought to characterize the role that each of these plays in altering chromatin accessibility in 2 closely related sea urchin species. Using hybrids of Heliocidaris erythrogramma and Heliocidaris tuberculata, and adapting a statistical framework previously developed for the analysis of cis and trans influences on the transcriptome, we examined how these mechanisms shape the regulatory landscape at 3 important developmental stages, and compared our results to similar analyses of the transcriptome. We found extensive cis- and trans-based influences on evolutionary changes in chromatin, with cis effects generally larger in effect. Evolutionary changes in accessibility and gene expression are correlated, especially when expression has a local genetic basis. Maternal influences appear to have more of an effect on chromatin accessibility than on gene expression, persisting well past the maternal-to-zygotic transition. Chromatin accessibility near gene regulatory network genes appears to be distinctly regulated, with trans factors appearing to play an outsized role in the configuration of chromatin near these genes. Together, our results represent the first attempt to quantify cis and trans influences on evolutionary divergence in chromatin configuration in an outbred natural study system and suggest that chromatin regulation is more genetically complex than was previously appreciated.
Electrospun fibers for the treatment of skin diseases
Authors: Anna-Lena Gürtler, Thomas Rades, Andrea Heinz
Journal: Journal of Controlled Release (2023)

Skin diseases are among the most common diseases in the global population and with the growth of the aging population, they represent an increasing burden to healthcare systems worldwide. Even though they are rarely life-threatening, the suffering for those affected is high due to the visibility and physical discomfort related to these diseases. Typical symptoms of skin diseases include an inflamed, swollen or itchy skin, and therefore, there is a high demand for effective therapy options. In recent years, electrospinning has attracted considerable interest in the field of drug delivery. The technique allows producing multifunctional drug-loaded fibrous patches from various natural and synthetic polymers with fiber diameters in the nano- and micrometer range, suitable for the treatment of a wide variety of skin diseases. The great potential of electrospun fiber patches not only lies in their tunable drug release properties and the possibility to entrap a variety of therapeutic compounds, but they also provide physical and mechanical protection to the impaired skin area, exhibit a high surface area, allow gas exchange, absorb exudate due to their porous structure and are cytocompatible and biodegradable. In the case of wound healing, cell adhesion is promoted due to the resemblance of the electrospun fibers to the structure of the native extracellular matrix. This review gives an overview of the potential applications of electrospun fibers in skin therapy. In addition to the treatment of bacterial, diabetic and burn wounds, focus is placed on inflammatory diseases such as atopic dermatitis and psoriasis, and therapeutic options for the treatment of skin cancer, acne vulgaris and herpes labialis are discussed. While we aim to emphasize the great potential of electrospun fiber patches for the treatment of skin diseases with this review paper, we also highlight challenges and limitations of current research in the field.
Current insights on the roles of gut microbiota in inflammatory bowel disease-associated extra-intestinal manifestations: pathophysiology and therapeutic targets
Authors: Yizhe Tie, Yongle Huang, Rirong Chen, Li Li, Minhu Chen, Shenghong Zhang
Journal: Gut Microbes (2023)

Inflammatory bowel disease (IBD) is a chronic, recurrent inflammatory disease of the gastrointestinal tract. In addition to digestive symptoms, patients with IBD may also develop extra-intestinal manifestations (EIMs), the etiology of which remains undefined. The gut microbiota has been reported to exert a critical role in the pathogenesis of IBD, with a similar pattern of gut dysbiosis observed between patients with IBD and those with EIMs. Therefore, it is hypothesized that the gut microbiota is also involved in the pathogenesis of EIMs. The potential mechanisms are presented in this review, including: 1) impaired gut barrier: dysbiosis induces pore formation in the intestinal epithelium, and activates pattern recognition receptors to promote local inflammation; 2) microbial translocation: intestinal pathogens, antigens, and toxins translocate via the impaired gut barrier into extra-intestinal sites; 3) molecular mimicry: certain microbial antigens share similar epitopes with self-antigens, inducing inflammatory responses targeting extra-intestinal tissues; 4) microbiota-related metabolites: dysbiosis results in the dysregulation of microbiota-related metabolites, which could modulate the differentiation of lymphocytes and cytokine production; 5) immunocytes and cytokines: immunocytes are over-activated and pro-inflammatory cytokines are excessively released. Additionally, we summarize microbiota-related therapies, including probiotics, prebiotics, postbiotics, antibiotics, and fecal microbiota transplantation, to promote better clinical management of IBD-associated EIMs.
A Novel Endoplasmic Reticulum‐Targeted Metal–Organic Framework–Confined Ruthenium (Ru) Nanozyme Regulation of Oxidative Stress for Central Post‐Stroke Pain
Authors: Qian Bai, Yupeng Han, Suliman Khan, Tingting Wu, Ying Yang, Yingying Wang, Hao Tang, Qing Li, Wei Jiang
Journal: Advanced Healthcare Materials (2023)

Abstract Central post‐stroke pain (CPSP) is a chronic neuropathic pain caused by cerebrovascular lesion or disfunction after stroke. Convincing evidence suggest that excessive reactive oxygen species (ROS), generated matrix metalloproteinase (MMPs) and neuroinflammation are largely involved in the development of pain. In this study, an effective strategy is reported for treating pain hypersensitivity using an endoplasmic reticulum (ER)‐targeted metal–organic framework (MOF)‐confined ruthenium (Ru) nanozyme. The Ru MOF is coated with a p‐dodecylbenzene sulfonamide (p‐DBSN) modified liposome with endoplasmic reticulum‐targeted function. The experimental results reveals that ROS, Emmprin, MMP‐2, and MMP‐9 are upregulated in the brain of CPSP mice, along with the elevated expression of inflammation markers such as TNF‐α and IL‐6. Compared to vehicle, one‐time intravenous administration of ER‐Ru MOF significantly reduces mechanical hypersensitivity after CPSP for three days. Overall, ER‐Ru MOF system can inhibit oxidative stress in the brain tissues of CPSP model, reduce MMPs expression, and suppress neuroinflammation response‐induced injury, resulting in satisfactory prevention and effective treatment of CPSP during a hemorrhagic stroke. The ER‐Ru MOF is expected to be useful for the treatment of neurological diseases associated with the vicious activation of ROS, based on the generality of the approach used in this study.
Combined Immunotherapy Improves Outcome for Replication-Repair-Deficient (RRD) High-Grade Glioma Failing Anti–PD-1 Monotherapy: A Report from the International RRD Consortium
Authors: Anirban Das, Nicholas R. Fernandez, Adrian Levine, Vanessa Bianchi, Lucie K. Stengs, Jiil Chung, Logine Negm, Jose Rafael Dimayacyac, Yuan Chang, Liana Nobre, Ayse B. Ercan, Santiago Sanchez-Ramirez, Sumedha Sudhaman, Melissa Edwards, Valerie Larouche, David Samuel, An Van Damme, David Gass, David S. Ziegler, Stefan S. Bielack, Carl Koschmann, Shayna Zelcer, Michal Yalon-Oren, Gadi Abede Campino, Tomasz Sarosiek, Kim E. Nichols, Rebecca Loret De Mola, Kevin Bielamowicz, Magnus Sabel, Charlotta A. Frojd, Matthew D. Wood, Jason M. Glover, Yi-Yen Lee, Magimairajan Vanan, Jenny K. Adamski, Sebastien Perreault, Omar Chamdine, Magnus Aasved Hjort, Michal Zapotocky, Fernando Carceller, Erin Wright, Ivana Fedorakova, Alexander Lossos, Ryuma Tanaka, Michael Osborn, Deborah T. Blumenthal, Melyssa Aronson, Ute Bartels, Annie Huang, Vijay Ramaswamy, David Malkin, Adam Shlien, Anita Villani, Peter B. Dirks, Trevor J. Pugh, Gad Getz, Yosef E. Maruvka, Derek S. Tsang, Birgit Ertl-Wagner, Cynthia Hawkins, Eric Bouffet, Daniel A. Morgenstern, Uri Tabori
Journal: Cancer Discovery (2023)

Abstract Immune checkpoint inhibition (ICI) is effective for replication-repair-deficient, high-grade gliomas (RRD-HGG). The clinical/biological impact of immune-directed approaches after failing ICI monotherapy is unknown. We performed an international study on 75 patients treated with anti–PD-1; 20 are progression free (median follow-up, 3.7 years). After second progression/recurrence (n = 55), continuing ICI-based salvage prolonged survival to 11.6 months (n = 38; P &amp;lt; 0.001), particularly for those with extreme mutation burden (P = 0.03). Delayed, sustained responses were observed, associated with changes in mutational spectra and the immune microenvironment. Response to reirradiation was explained by an absence of deleterious postradiation indel signatures (ID8). CTLA4 expression increased over time, and subsequent CTLA4 inhibition resulted in response/stable disease in 75%. RAS–MAPK-pathway inhibition led to the reinvigoration of peripheral immune and radiologic responses. Local (flare) and systemic immune adverse events were frequent (biallelic mismatch-repair deficiency &amp;gt; Lynch syndrome). We provide a mechanistic rationale for the sustained benefit in RRD-HGG from immune-directed/synergistic salvage therapies. Future approaches need to be tailored to patient and tumor biology. Significance: Hypermutant RRD-HGG are susceptible to checkpoint inhibitors beyond initial progression, leading to improved survival when reirradiation and synergistic immune/targeted agents are added. This is driven by their unique biological and immune properties, which evolve over time. Future research should focus on combinatorial regimens that increase patient survival while limiting immune toxicity. This article is featured in Selected Articles from This Issue, p. 201